This grant application proposed the continuation of our integrated program of clinical and pharmacological reseaach to explore both the underlying biochemical pathophysiology of the affective disorders as well as the possible mechanisms of action of drugs (and other somatic interventions) used in their treatment. This research, which will test a number of specific hypotheses (as described in detail in text of this application), can be subsumed under several broad categories: 1. Studies of biological difference (including measures of biogenic amine metabolism and sleep stages) in clinically defined subtypes of depressive disorders. 2. Studies of clinical differences in groupings of depressed patients defined by various biological criteia (including measures of biogenic amine metabolism and sleep stages). 3. Studies of the relationships among various biological variables (including measures of biogenic amine metabolism and sleep stages) in patients with depressive disorders. 4. Studies of pretreatment biologicaland clinical variables as predictors of response to antidepressand pharmacotherapy. 5. Longitudinal studies of the changes in biogenic amine metabolism and sleep stages associated with drug administration or changes in clinical state in patients with depressions of manias. 6. Studies of the changes in norepinephrine turnover (as evidenced by levels of MHPG-sulfate) in rat brain regions after acute and chronic administration of lithium salts, electroconvulsive shock and tricyclic antidepressant drugs.